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1.  Dietary Protein Intake and Coronary Heart Disease in a Large Community Based Cohort: Results from the Atherosclerosis Risk in Communities (ARIC) Study 
PLoS ONE  2014;9(10):e109552.
Background
Prospective data examining the relationship between dietary protein intake and incident coronary heart disease (CHD) are inconclusive. Most evidence is derived from homogenous populations such as health professionals. Large community-based analyses in more diverse samples are lacking.
Methods
We studied the association of protein type and major dietary protein sources and risk for incident CHD in 12,066 middle-aged adults (aged 45–64 at baseline, 1987–1989) from four U.S. communities enrolled in the Atherosclerosis Risk in Communities (ARIC) Study who were free of diabetes mellitus and cardiovascular disease at baseline. Dietary protein intake was assessed at baseline and after 6 years of follow-up by food frequency questionnaire. Our primary outcome was adjudicated coronary heart disease events or deaths with following up through December 31, 2010. Cox proportional hazard models with multivariable adjustment were used for statistical analyses.
Results
During a median follow-up of 22 years, there were 1,147 CHD events. In multivariable analyses total, animal and vegetable protein were not associated with an increased risk for CHD before or after adjustment. In food group analyses of major dietary protein sources, protein intake from red and processed meat, dairy products, fish, nuts, eggs, and legumes were not significantly associated with CHD risk. The hazard ratios [with 95% confidence intervals] for risk of CHD across quintiles of protein from poultry were 1.00 [ref], 0.83 [0.70–0.99], 0.93 [0.75–1.15], 0.88 [0.73–1.06], 0.79 [0.64–0.98], P for trend  = 0.16). Replacement analyses evaluating the association of substituting one source of dietary protein for another or of decreasing protein intake at the expense of carbohydrates or total fats did not show any statistically significant association with CHD risk.
Conclusion
Based on a large community cohort we found no overall relationship between protein type and major dietary protein sources and risk for CHD.
doi:10.1371/journal.pone.0109552
PMCID: PMC4193805  PMID: 25303709
2.  Associations Between Metabolomic Compounds and Incident Heart Failure Among African Americans: The ARIC Study 
American Journal of Epidemiology  2013;178(4):534-542.
Heart failure is more prevalent among African Americans than in the general population. Metabolomic studies among African Americans may efficiently identify novel biomarkers of heart failure. We used untargeted methods to measure 204 stable serum metabolites and evaluated their associations with incident heart failure hospitalization (n = 276) after a median follow-up of 20 years (1987–2008) by using Cox regression in data from 1,744 African Americans aged 45–64 years without heart failure at baseline from the Jackson, Mississippi, field center of the Atherosclerosis Risk in Communities (ARIC) Study. After adjustment for established risk factors, we found that 16 metabolites (6 named with known structural identities and 10 unnamed with unknown structural identities, the latter denoted by using the format X-12345) were associated with incident heart failure (P < 0.0004 based on a modified Bonferroni procedure). Of the 6 named metabolites, 4 are involved in amino acid metabolism, 1 (prolylhydroxyproline) is a dipeptide, and 1 (erythritol) is a sugar alcohol. After additional adjustment for kidney function, 2 metabolites remained associated with incident heart failure (for metabolite X-11308, hazard ratio = 0.75, 95% confidence interval: 0.65, 0.86; for metabolite X-11787, hazard ratio = 1.23, 95% confidence interval: 1.10, 1.37). Further structural analysis revealed X-11308 to be a dihydroxy docosatrienoic acid and X-11787 to be an isoform of either hydroxyleucine or hydroxyisoleucine. Our metabolomic analysis revealed novel biomarkers associated with incident heart failure independent of traditional risk factors.
doi:10.1093/aje/kwt004
PMCID: PMC3736751  PMID: 23788672
heart failure; metabolomics; risk factors
3.  DASH Eating Pattern Is Associated with Favorable Left Ventricular Function in the Multi-Ethnic Study of Atherosclerosis 
Objective
Potential associations between consistency with the Dietary Approaches to Stop Hypertension (DASH) diet and preclinical stages of heart failure (HF) in a large multiethnic cohort have not been evaluated. This study sought to determine the cross-sectional relationship between the DASH eating pattern and left ventricular (LV) function in the Multi-Ethnic Study of Atherosclerosis (MESA).
Design
A total of 4506 men and women from four ethnic groups (40% white, 24% African American, 22% Hispanic American, and 14% Chinese American) aged 45–84 years and free of clinical cardiovascular disease (CVD) were studied. Diet was assessed using a validated food-frequency questionnaire. LV functional parameters including end-diastolic volume, stroke volume, and LV ejection fraction were measured by magnetic resonance imaging. Multivariate analyses were conducted to examine the association between LV function and DASH eating pattern (including high consumption of fruits, vegetables, whole grains, poultry, fish, nuts, and low-fat dairy products and low consumption of red meat, sweets, and sugar-sweetened beverages).
Results
A 1-unit increase in DASH eating pattern score was associated with a 0.26 ml increase in end-diastolic volume and increases of 0.10 ml/m2 in stroke volume, adjusted for key confounders. A 1-unit increase in DASH eating pattern score was also associated with a 0.04% increase in ejection fraction, but the relationship was marginally significant (p = 0.08).
Conclusions
In this population, greater DASH diet consistency is associated with favorable LV function. DASH dietary patterns could be protective against HF.
PMCID: PMC4119794  PMID: 23756584
DASH diet; LV function; preclinical heart failure
4.  METABOLOMICS AND INCIDENT HYPERTENSION AMONG AFRICAN AMERICANS: THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY 
Hypertension  2013;62(2):398-403.
Development of hypertension is influenced by genes, environmental effects and their interactions, and the human metabolome is a measurable manifestation of gene-environment interaction. We explored the metabolomic antecedents of developing incident hypertension in a sample of African Americans, a population with a high prevalence of hypertension and its comorbidities. We examined 896 (565 females, aged 45–64 years) African American normotensives from the Atherosclerosis Risk in Communities (ARIC) Study, whose metabolome was measured in serum collected at the baseline examination and analyzed by high throughput methods. The analyses presented here focus on 204 stably measured metabolites over a period of 4–6 weeks. Weibull parametric models considering interval censored data were used to assess the hazard ratio for incident hypertension. We used a modified Bonferroni correction accounting for the correlations among metabolites to define a threshold for statistical significance (p<3.9×10−4). During 10-years of follow-up, 38% of baseline normotensives developed hypertension (N=344). With adjustment for traditional risk factors and estimated glomerular filtration rate, each +1-standard deviation difference in baseline 4-hydroxyhippurate, a product of gut microbial fermentation, was associated with 17% higher risk of hypertension (p=2.5×10−4), which remained significant after adjusting for both baseline systolic and diastolic blood pressure (p=3.8×10−4). After principal component analyses, a sex steroids pattern was significantly associated with risk of incident hypertension (highest versus lowest quintile hazard ratio, 1.72; 95% CI, 1.05 to 2.82; p for trend=0.03), and stratified analyses suggested that this association was consistent in both genders. Metabolomic analyses identify novel pathways in the etiology of hypertension.
doi:10.1161/HYPERTENSIONAHA.113.01166
PMCID: PMC3789066  PMID: 23774226
metabolomics; hypertension; African Americans; risk factor
5.  Genome-Wide Association Study of a Heart Failure-Related Metabolomic Profile among African Americans in the Atherosclerosis Risk in Communities (ARIC) Study 
Genetic epidemiology  2013;37(8):840-845.
Both the prevalence and incidence of heart failure (HF) are increasing, especially among African-Americans, but no large-scale, genome-wide association study (GWAS) of HF-related metabolites have been reported. We sought to identify novel genetic variants that are associated with metabolites previously reported to relate to HF incidence. GWASs of three metabolites identified previously as risk factors for incident HF (pyroglutamine, dihydroxy docosatrienoic acid and X-11787, being either hydroxy-leucine or hydroxy-isoleucine) were performed in 1260 African-Americans free of HF at the baseline examination of the Atherosclerosis Risk in Communities (ARIC) study. A significant association on chromosome 5q33 (rs10463316, MAF = 0.358, p-value = 1.92×10−10) was identified for pyroglutamine. One region on chromosome 2p13 contained a nonsynonymous substitution in N-acetyltransferase 8 (NAT8) was associated with X-11787 (rs13538, MAF = 0.481, p-value = 1.71×10−23). The smallest p-value for dihydroxy docosatrienoic acid was rs4006531 on chromosome 8q24 (MAF = 0.400, p-value = 6.98×10−7). None of the above SNPs were individually associated with incident HF, but a genetic risk score (GRS) created by summing the most significant risk alleles from each metabolite detected 11% greater risk of HF per allele. In summary, we identified three loci associated with previously reported HF-related metabolites. Further use of metabolomics technology will facilitate replication of these findings in independent samples.
doi:10.1002/gepi.21752
PMCID: PMC4079107  PMID: 23934736
metabolomics; genome-wide association; African-Americans; heart failure
6.  Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake1234 
Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7).
Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
doi:10.3945/ajcn.112.052183
PMCID: PMC3652928  PMID: 23636237
7.  Relations of the Mediterranean dietary pattern with insulin resistance and diabetes incidence in the Multi-Ethnic Study of Atherosclerosis (MESA) 
The British journal of nutrition  2012;109(8):1490-1497.
Type 2 diabetes is a highly prevalent but preventable disorder. We assessed the association between an a priori Mediterranean diet score (MeDiet) and fasting glucose and insulin at baseline and incident type 2 diabetes after 6-year follow-up in MESA. Dietary intake was measured at baseline by a 127-item food frequency questionnaire in 5,390 men and women aged 45-84 years free of prevalent diabetes and clinical CVD. A MeDiet score was created based on intake of 10 food components: vegetables, whole grains, nuts, legumes, fruits, ratio of monounsaturated to saturated fat, red and processed meat, dairy, fish and alcohol. Multivariable linear and proportional hazard models were used to estimate the association of MeDiet, categorized in quintiles, with baseline insulin and glucose, and incident diabetes, respectively. Models adjusted for demographic, physiologic and behavioral characteristics. After multivariable adjustment, individuals with a higher MeDiet score had lower baseline mean (95% CI) insulin levels [mean Q1: = 5.8 (5.6-6.0) umol/l; mean Q5: = 4.8 (4.6-5.0) umol/l; p-trend= <0.0001]. A higher MeDiet score was also associated with significantly lower glucose levels after basic adjustment, but was attenuated after adjustment for waist circumference. During follow-up, 412 incident diabetes events accrued. MeDiet was not significantly related to risk of incident diabetes (p-trend=0.64). In summary, greater consistency with a Mediterranean-style diet, reflected by a higher a priori Mediterranean diet score, was cross-sectionally associated with lower insulin levels among non-diabetics, and lower blood glucose prior to adjustment for obesity, but not with lower incidence of diabetes.
doi:10.1017/S0007114512003339
PMCID: PMC4002212  PMID: 22932232
8.  Dietary patterns are associated with plasma F2-isoprostanes in an observational cohort study of adults 
Free radical biology & medicine  2012;57:10.1016/j.freeradbiomed.2012.08.574.
Associations between individual foods or nutrients and oxidative markers have been reported. Comprehensive measures of food intake may be uniquely informative, given the complexity of oxidative systems and the possibility for antioxidant synergies. We quantified associations over a 20 y history between 3 food-based dietary patterns, summary measures of whole diet, and a plasma biomarker of lipid peroxidation, F2-isoprostanes in a cohort of Americans, aged 18–30 at year 0 (1985–86). We assessed diet at years 0, 7, and 20 through a detailed history of past-month food consumption and supplement use, and measured plasma F2-isoprostanes at years 15 and 20. We created 3 different dietary patterns: 1) a priori (“a priori diet quality score”) based on hypothesized healthy foods, 2) an empirical pattern reflecting high fruit and vegetable intake (“fruit-veg”), and 3) an empirical pattern reflecting high meat intake (“meat”). We used linear regression to estimate associations between each dietary pattern and plasma F2-isoprostanes cross-sectionally (at year 20, n=2,736) and prospectively (year 0/7 average diet and year 15/20 average F2-isoprostanes, n=2,718), adjusting for age, sex, race, total energy intake, education, smoking, body mass index (BMI), waist circumference, physical activity, and supplement use. In multivariable-adjusted cross-sectional analysis, the a priori diet quality score and the fruit-veg diet pattern were negatively, and the meat pattern positively, associated with F2-isoprostanes (all p-values<0.001). These associations remained statistically significant in prospective analysis. Our findings suggest that a long-term adherence to a diet rich in fruits and vegetables and low in red meat may decrease lipid peroxidation.
doi:10.1016/j.freeradbiomed.2012.08.574
PMCID: PMC3872789  PMID: 22982044
cohort; epidemiology; diet; oxidative stress
9.  Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway: Results from the CHARGE Consortium 
Background
Palmitic acid(16:0), stearic acid(18:0), palmitoleic acid(16:1n-7), and oleic acid(18:1n-9) are major saturated and mono-unsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis (DNL) and are the main saturated and mono-unsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes and coronary heart disease.
Methods and Results
Genome-wide association studies were conducted in 5 population-based cohorts comprising 8,961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these four fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of one or more of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0(P=2.7×10-11) and lower 18:0(P=2.2×10-18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6×10-13) and 18:1n-9(P=2.2×10-32), and lower 18:0(P =1.3×10-20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8×10-9). GCKR(glucokinase regulator, P =9.8×10-10) and HIF1AN(factor inhibiting hypoxia-inducible factor-1, P=5.7×10-9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1(polycystic kidney disease 2-like 1, P=5.7×10-15) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1×10-8).
Conclusion
Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of four fatty acids in the DNL pathway. These results expand our knowledge of genetic factors relevant to DNL and fatty acid biology.
doi:10.1161/CIRCGENETICS.112.964619
PMCID: PMC3891054  PMID: 23362303
epidemiology; fatty acids; genome-wide association study
10.  Ideal Cardiovascular Health is Inversely Associated with Incident Cancer: The Atherosclerosis Risk in Communities Study 
Circulation  2013;127(12):1270-1275.
Background
The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of their 2020 Strategic Impact Goals. We examined if adherence to ideal levels of the seven AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17-19 years of follow-up.
Methods and Results
After exclusions for missing data and prevalent cancer, 13,253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to seven AHA cardiovascular health metrics. Combined cancer incidence (excluding non-melanoma skin cancers) from 1987-2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant (p-trend< .0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6-7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5-6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics (p-trend = .03).
Conclusions
Adherence to the seven ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence.
doi:10.1161/CIRCULATIONAHA.112.001183
PMCID: PMC3685848  PMID: 23509058
ideal cardiovascular health; cancer; prevention
11.  Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts 
American Journal of Epidemiology  2012;177(2):103-115.
Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = −0.004 mmol/L, 95% confidence interval: −0.005, −0.003) and FI (β = −0.008 ln-pmol/L, 95% confidence interval: −0.009, −0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.
doi:10.1093/aje/kws297
PMCID: PMC3707424  PMID: 23255780
diabetes; dietary pattern; gene-environment interaction; glucose; insulin
12.  Dietary phosphorus is associated with a significant increase in left ventricular mass 
Kidney international  2013;83(4):707-714.
Dietary phosphorus consumption has risen steadily in the United States. Oral phosphorus loading alters key regulatory hormones and impairs vascular endothelial function which may lead to an increase in left ventricular mass (LVM). We investigated the association of dietary phosphorus with LVM in 4,494 participants from the Multi-Ethnic Study of Atherosclerosis, a community-based study of individuals free of known cardiovascular disease. The intake of dietary phosphorus was estimated using a 120-item food frequency questionnaire and the LVM was measured using magnetic resonance imaging. Regression models were used to determine associations of estimated dietary phosphorus with LVM and left ventricular hypertrophy (LVH). Mean estimated dietary phosphorus intake was 1,167 mg/day in men and 1,017 mg/day in women. After adjustment for demographics, dietary sodium, total calories, lifestyle factors, comorbidities, and established LVH risk factors, each quintile increase in the estimated dietary phosphate intake was associated with an estimated 1.1 gram greater LVM. The highest gender-specific dietary phosphorus quintile was associated with an estimated 6.1 gram greater LVM compared to the lowest quintile. Higher dietary phosphorus intake was associated with greater odds of LVH among women, but not men. These associations require confirmation in other studies.
doi:10.1038/ki.2012.303
PMCID: PMC3612378  PMID: 23283134
Phosphorus; phosphate; diet; consumption; left ventricular mass; left ventricular hypertrophy
13.  Associations of Socioeconomic Status and Processed Food Intake with Serum Phosphorus in Community-Living Adults: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Objective
Higher serum phosphorus concentrations are associated with cardiovascular disease events and mortality. Low socioeconomic status is linked with higher serum phosphorus, but the reasons are unclear. Poor individuals disproportionately consume inexpensive processed foods commonly enriched with phosphorus-based food preservatives. Accordingly, we hypothesized that excess intake of these foods accounts for a relationship between lower socioeconomic status and higher serum phosphorus.
Design
Cross-sectional analysis.
Setting and Participants
We examined a random cohort of 2,664 participants with available phosphorus measurements in the Multi-Ethnic Study of Atherosclerosis, a community-based sample of individuals free of clinically apparent cardiovascular disease from across the United States.
Predictor Variables
Socioeconomic status, the intake of foods commonly enriched with phosphorus additives (processed meats, sodas) and frequency of fast food consumption.
Outcomes
Fasting morning serum phosphorus concentrations.
Results
In unadjusted analyses, lower income and lower educational achievement categories were associated with modestly higher serum phosphorus (by 0.02 to 0.10 mg/dL, P < 0.05 for all). These associations were attenuated in models adjusted for demographic and clinical factors, almost entirely due to adjustment for female gender. There were no statistically significant associations of processed meat intake or frequency of fast-food consumption with serum phosphorus in multivariable-adjusted analyses. In contrast, each serving per day higher soda intake was associated with 0.02 mg/dl lower serum phosphorus (95% confidence interval, −0.04, −0.01).
Conclusions
Greater intake of foods commonly enriched with phosphorus additives was not associated with higher serum phosphorus in a community-living sample with largely preserved kidney function. These results suggest that excess intake of processed and fast foods may not impact fasting serum phosphorus concentrations among individuals without kidney disease.
doi:10.1053/j.jrn.2011.08.008
PMCID: PMC3321388  PMID: 22217539
phosphorus; socioeconomic status; nutrition
14.  Biomarkers of Dairy Fatty Acids and Risk of Cardiovascular Disease in the Multi‐Ethnic Study of Atherosclerosis 
Background
Evidence regarding the role of dairy fat intake in cardiovascular disease (CVD) has been mixed and inconclusive. Most earlier studies have used self‐reported measures of dietary intake and focused on relatively racially homogeneous populations. Circulating biomarkers of dairy fat in a multiethnic cohort provide objective measures of dairy fat intake and facilitate conclusions relevant to populations with different diets and susceptibility to CVD.
Methods and Results
In a multiethnic cohort of 2837 US adults aged 45 to 84 years at baseline (2000–2002), phospholipid fatty acids including 15:0, 14:0, and trans‐16:1n7 were measured using standardized methods, and the incidence of CVD prospectively adjudicated. Self‐reported whole‐fat dairy and butter intakes had strongest associations with 15:0, rather than 14:0 or trans‐16:1n7. In multivariate models including demographics and lifestyle and dietary habits, each SD‐unit of 15:0 was associated with 19% lower CVD risk (hazard ratio [95% CI] 0.81 [0.68 to 0.98]) and 26% lower coronary heart disease (CHD) risk (0.74 [0.60 to 0.92]). Associations were strengthened after mutual adjustment for 14:0 and trans‐16:1n‐7 and were similar after adjustment for potential mediators. Plasma phospholipid 14:0 and trans‐16:1n‐7 were not significantly associated with incident CVD or CHD. All findings were similar in white, black, Hispanic, and Chinese American participants.
Conclusion
Plasma phospholipid 15:0, a biomarker of dairy fat, was inversely associated with incident CVD and CHD, while no association was found with phospholipid 14:0 and trans‐16:1n‐7. These findings support the need for further investigation of CVD effects of dairy fat, dairy‐specific fatty acids, and dairy products in general.
doi:10.1161/JAHA.113.000092
PMCID: PMC3828802  PMID: 23868191
cardiovascular diseases; dairy fat; diet; fatty acids
15.  Associations of Organic Produce Consumption with Socioeconomic Status and the Local Food Environment: Multi-Ethnic Study of Atherosclerosis (MESA) 
PLoS ONE  2013;8(7):e69778.
Neighborhood characteristics, such as healthy food availability, have been associated with consumption of healthy food. Little is known about the influence of the local food environment on other dietary choices, such as the decision to consume organic food. We analyzed the associations between organic produce consumption and demographic, socioeconomic and neighborhood characteristics in 4,064 participants aged 53–94 in the Multi-Ethnic Study of Atherosclerosis using log-binomial regression models. Participants were classified as consuming organic produce if they reported eating organic fruits and vegetables either “sometimes” or “often or always”. Women were 21% more likely to consume organic produce than men (confidence interval [CI]: 1.12–1.30), and the likelihood of organic produce consumption was 13% less with each additional 10 years of age (CI: 0.84–0.91). Participants with higher education were significantly more likely to consume organic produce (prevalence ratios [PR] were 1.05 with a high school education, 1.39 with a bachelor's degree and 1.68 with a graduate degree, with less than high school as the reference group [1.00]). Per capita household income was marginally associated with produce consumption (p = 0.06), with the highest income category more likely to consume organic produce. After adjustment for these individual factors, organic produce consumption was significantly associated with self-reported assessment of neighborhood produce availability (PR: 1.07, CI: 1.02–1.11), with an aggregated measure of community perception of the local food environment (PR: 1.08, CI: 1.00–1.17), and, to a lesser degree, with supermarket density (PR: 1.02: CI: 0.99–1.05). This research suggests that both individual-level characteristics and qualities of the local food environment are associated with having a diet that includes organic food.
doi:10.1371/journal.pone.0069778
PMCID: PMC3729963  PMID: 23936098
16.  A Diet Pattern with More Dairy and Nuts, but Less Meat Is Related to Lower Risk of Developing Hypertension in Middle-Aged Adults: The Atherosclerosis Risk in Communities (ARIC) Study 
Nutrients  2013;5(5):1719-1733.
Dietary intake among other lifestyle factors influence blood pressure. We examined the associations of an “a priori” diet score with incident high normal blood pressure (HNBP; systolic blood pressure (SBP) 120–139 mmHg, or diastolic blood pressure (DBP) 80–89 mmHg and no antihypertensive medications) and hypertension (SBP ≥ 140 mmHg, DBP ≥ 90 mmHg, or taking antihypertensive medication). We used proportional hazards regression to evaluate this score in quintiles (Q) and each food group making up the score relative to incident HNBP or hypertension over nine years in the Atherosclerosis Risk of Communities (ARIC) study of 9913 African-American and Caucasian adults aged 45–64 years and free of HNBP or hypertension at baseline. Incidence of HNBP varied from 42.5% in white women to 44.1% in black women; and incident hypertension from 26.1% in white women to 40.8% in black women. Adjusting for demographics and CVD risk factors, the “a priori” food score was inversely associated with incident hypertension; but not HNBP. Compared to Q1, the relative hazards of hypertension for the food score Q2–Q5 were 0.97 (0.87–1.09), 0.91 (0.81–1.02), 0.91 (0.80–1.03), and 0.86 (0.75–0.98); ptrend = 0.01. This inverse relation was largely attributable to greater intake of dairy products and nuts, and less meat. These findings support the 2010 Dietary Guidelines to consume more dairy products and nuts, but suggest a reduction in meat intake.
doi:10.3390/nu5051719
PMCID: PMC3708346  PMID: 23698164
diet pattern; healthy food score; hypertension; high normal blood pressure
17.  Associations of dairy intake with CT lung density and lung function 
Objective
Dairy products contain vitamin D and other nutrients that may be beneficial for lung function, but are also high in fats that may have mixed effects on lung function. However, the overall associations of dairy intake with lung density and lung function have not been studied.
Methods
We examined the cross-sectional relations between dairy intake and CT lung density and lung function in the Multi-Ethnic Study of Atherosclerosis (MESA). Total, low-fat and high-fat dairy intakes were quantified from food frequency questionnaire responses of men and women, aged 45–84 years, free of clinical cardiovascular disease. The MESA-Lung Study assessed CT lung density from cardiac CT imaging and prebronchodilator spirometry among 3,965 MESA participants.
Results
Total dairy intake was inversely associated with apical-basilar difference in percent emphysema and positively associated with FVC (the multivariate-adjusted mean difference between the highest and the lowest quintile of total dairy intake was −0.92 (p for trend=0.04) for apical-basilar difference in percent emphysema and 72.0 mL (p=0.01) for FVC). Greater low-fat dairy intake was associated with higher alpha (higher alpha values indicate less emphysema) and lower apical-basilar difference in percent emphysema (corresponding differences in alpha and apical-basilar difference in percent emphysema were 0.04 (p=0.02) and −0.98 (p=0.01) for low-fat dairy intake, respectively). High-fat dairy intake was not associated with lung density measures. Greater low- or high-fat dairy intake was not associated with higher FEV1, FVC and FEV1/FVC.
Conclusions
Higher low-fat dairy intake but not high-fat dairy intake was associated with moderately improved CT lung density.
PMCID: PMC3616890  PMID: 21504976
dairy intake; lung density; emphysema; lung function; chronic obstructive pulmonary disease
18.  Total Zinc Intake May Modify the Glucose-Raising Effect of a Zinc Transporter (SLC30A8) Variant 
Diabetes  2011;60(9):2407-2416.
OBJECTIVE
Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.
RESEARCH DESIGN AND METHODS
We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.
RESULTS
We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: −0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: −0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.
CONCLUSIONS
Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.
doi:10.2337/db11-0176
PMCID: PMC3161318  PMID: 21810599
19.  Sex Differences in Subclinical Atherosclerosis by Race/Ethnicity in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2011;174(2):165-172.
Sex differences in cardiovascular disease mortality are more pronounced among non-Hispanic whites than other racial/ethnic groups, but it is unknown whether this variation is present in the earlier subclinical stages of disease. The authors examined racial/ethnic variation in sex differences in coronary artery calcification (CAC) and carotid intimal media thickness at baseline in 2000–2002 among participants (n = 6,726) in the Multi-Ethnic Study of Atherosclerosis using binomial and linear regression. Models adjusted for risk factors in several stages: age, traditional cardiovascular disease risk factors, behavioral risk factors, psychosocial factors, and adult socioeconomic position. Women had a lower prevalence of any CAC and smaller amounts of CAC when present than men in all racial/ethnic groups. Sex differences in the prevalence of CAC were more pronounced in non-Hispanic whites than in African Americans and Chinese Americans after adjustment for traditional cardiovascular disease risk factors, and further adjustment for behavioral factors, psychosocial factors, and socioeconomic position did not modify these results (for race/sex, Pinteraction = 0.047). Similar patterns were observed for amount of CAC among adults with CAC. Racial/ethnic variation in sex differences for carotid intimal media thickness was less pronounced. In conclusion, coronary artery calcification is differentially patterned by sex across racial/ethnic groups.
doi:10.1093/aje/kwr088
PMCID: PMC3167681  PMID: 21685409
calcification, physiologic; continental population groups; coronary vessels; sex; social class
20.  Fish, Fish-Derived n-3 Fatty Acids, and Risk of Incident Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study 
PLoS ONE  2012;7(5):e36686.
Background
Results of observational and experimental studies investigating the association between intake of long-chain n-3 polyunsaturated fatty acids (PUFAs) and risk of atrial fibrillation (AF) have been inconsistent.
Methods
We studied the association of fish and the fish-derived n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with the risk of incident AF in individuals aged 45–64 from the Atherosclerosis Risk in Communities (ARIC) cohort (n = 14,222, 27% African Americans). Intake of fish and of DHA and EPA were measured via food frequency questionnaire. Plasma levels of DHA and EPA were measured in phospholipids in a subset of participants (n = 3,757). Incident AF was identified through the end of 2008 using ECGs, hospital discharge codes and death certificates. Cox proportional hazards regression was used to estimate hazard ratios of AF by quartiles of n-3 PUFAs or by fish intake.
Results
During the average follow-up of 17.6 years, 1,604 AF events were identified. In multivariable analyses, total fish intake and dietary DHA and EPA were not associated with AF risk. Higher intake of oily fish and canned tuna was associated with a nonsignificant lower risk of AF (p for trend = 0.09). Phospholipid levels of DHA+EPA were not related to incident AF. However, DHA and EPA showed differential associations with AF risk when analyzed separately, with lower risk of AF in those with higher levels of DHA but no association between EPA levels and AF risk.
Conclusions
In this racially diverse sample, dietary intake of fish and fish-derived n-3 fatty acids, as well as plasma biomarkers of fish intake, were not associated with AF risk.
doi:10.1371/journal.pone.0036686
PMCID: PMC3343018  PMID: 22570739
21.  Community Prevalence of Ideal Cardiovascular Health, by the AHA Definition, and Relation to Cardiovascular Disease Incidence 
Objectives
To estimate the prevalence of ideal cardiovascular health and its relation to incident cardiovascular disease (CVD).
Background
An American Heart Association committee recently set a goal to improve the cardiovascular heath of Americans by 20% by 2020. The committee developed definitions of “ideal,” “intermediate,” or “poor” cardiovascular health for adults and children based on seven CVD risk factors or health behaviors.
Methods
We used data from the Atherosclerosis Risk in Communities (ARIC) Study cohort, aged 45–64 years, to estimate the prevalence of ideal cardiovascular health in 1987–89 and the corresponding incidence rates of CVD. Incident CVD comprised stroke, heart failure, myocardial infarction, or fatal coronary disease.
Results
Among 12,744 participants initially free of CVD, only 0.1% had ideal cardiovascular health, 17.4% had intermediate cardiovascular health, and 82.5% had poor cardiovascular health. CVD incidence rates through 2007 showed a graded relation with the ideal, intermediate, and poor categories and with the number of ideal health metrics present: rates were one tenth as high in those with six ideal health metrics (3.9 per 1,000 person-years) compared with zero ideal health metrics (37.1 per 1,000 person-years).
Conclusions
In this community-based sample, few adults in 1987–9 had ideal cardiovascular health by the new AHA definition. Those who had the best levels of cardiovascular health nevertheless sustained relatively few events. Clearly, to achieve the AHA goal of improving cardiovascular health by 20% by 2020, we will need to redouble nationwide primordial prevention efforts at the population and individual levels.
doi:10.1016/j.jacc.2010.11.041
PMCID: PMC3093047  PMID: 21492767
epidemiology; risk factors; cardiovascular disease; stroke; coronary disease
22.  Interactions of Dietary Whole-Grain Intake With Fasting Glucose– and Insulin-Related Genetic Loci in Individuals of European Descent 
Diabetes Care  2010;33(12):2684-2691.
OBJECTIVE
Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.
RESEARCH DESIGN AND METHODS
Via meta-analysis of data from 14 cohorts comprising ∼48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.
RESULTS
Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: −0.009 mmol/l glucose [−0.013 to −0.005], P < 0.0001 and −0.011 pmol/l [ln] insulin [−0.015 to −0.007], P = 0.0003). No interactions met our multiple testing–adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.
CONCLUSIONS
Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
doi:10.2337/dc10-1150
PMCID: PMC2992213  PMID: 20693352
23.  Invited Commentary: Gene × Lifestyle Interactions and Complex Disease Traits—Inferring Cause and Effect From Observational Data, Sine Qua Non 
American Journal of Epidemiology  2010;172(9):992-997.
Observational epidemiology has made outstanding contributions to the discovery and elucidation of relations between lifestyle factors and common complex diseases such as type 2 diabetes. Recent major advances in the understanding of the human genetics of this disease have inspired studies that seek to determine whether the risk conveyed by bona fide risk loci might be modified by lifestyle factors such as diet composition and physical activity levels. A major challenge is to determine which of the reported findings are likely to represent causal interactions and which might be explained by other factors. The authors of this commentary use the Bradford-Hill criteria, a set of tried-and-tested guidelines for causal inference, to evaluate the findings of a recent study on interaction between variation at the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) locus and total energy intake with respect to prevalent metabolic syndrome and hemoglobin A1c levels in a cohort of 313 Japanese men. The current authors conclude that the study, while useful for hypothesis generation, does not provide overwhelming evidence of causal interactions. They overview ways in which future studies of gene × lifestyle interactions might overcome the limitations that motivated this conclusion.
doi:10.1093/aje/kwq280
PMCID: PMC2984255  PMID: 20847104
CDKAL1 protein, human; energy intake; hemoglobin A1c protein, human; Japan; metabolic syndrome X
24.  Associations between dietary patterns and flow cytometry-measured biomarkers of inflammation and cellular activation in the Atherosclerosis Risk in Communities (ARIC) Carotid Artery MRI Study 
Atherosclerosis  2010;212(1):260-267.
Background
Specific foods and overall dietary patterns are associated with soluble biomarkers of systemic inflammation and endothelial activation. However, no large epidemiological studies have evaluated relationships between such dietary factors and cell-specific markers of activation and inflammation as measured by flow cytometry.
Methods
Cell aggregates and multiple platelet and leukocyte markers were quantified by flow cytometry in fresh whole blood from 1,101 white adults participating in the Carotid Artery MRI study, a subset of the larger Atherosclerosis Risk in Communities (ARIC) study. Two dietary patterns (“Healthy” and “Western”) were empirically-derived via principal components analysis using data collected by food frequency questionnaire. Cross-sectional associations between dietary patterns and flow cytometry-measured biomarkers were evaluated, adjusting for demographics and lifestyle factors, including medications use.
Results
After multivariable adjustment, monocyte lipopolysaccharide receptor (CD14), monocyte toll-like receptor-2, and platelet glycoprotein IIb (CD41) showed inverse associations with the Healthy dietary pattern (p = 0.01, 0.04, and 0.01, respectively). In contrast, the Western dietary pattern was positively associated with CD41 and platelet-granulocyte aggregates (p = 0.01 and 0.04, respectively). Independent of other dietary factors, alcohol consumption was inversely associated with levels of pan leukocyte marker (CD45), P-selectin (CD62P) on PLA1 and on PLA2 platelets, and platelet-monocyte, platelet-granulocyte, and platelet-lymphocyte aggregates.
Conclusion
Dietary patterns and alcohol intake were each cross-sectionally associated with select markers of cellular activation and inflammation measured by flow cytometry. These data are consistent with the hypothesis that holistic measures of dietary intake are associated with inflammation.
doi:10.1016/j.atherosclerosis.2010.04.026
PMCID: PMC2933270  PMID: 20537646
dietary patterns; flow cytometry; inflammation; endothelial activation; biomarkers; cardiovascular disease
25.  Associations of Plasma Phospholipid Omega-6 and Omega-3 Polyunsaturated Fatty Acid Levels and MRI Measures of Cardiovascular Structure and Function: The Multiethnic Study of Atherosclerosis 
Background. The association between plasma omega-6 fatty acids and cardiovascular disease (CVD) is unclear, and discrepancy remains concerning the cardiovascular benefit of the omega-3 fatty acid alpha-linolenic acid. Methods. Associations of plasma phospholipid fatty acid levels (arachidonic acid, linoleic acid, eicosapentaenoic acid, docosahexaenoic acid (DHA), and alpha-linolenic acid) with cardiac magnetic resonance imaging measures of left ventricular (LV) mass, LV volume, ejection fraction, stroke volume, and aortic distensibility were investigated in 1,274 adults. Results. Results of multivariate analysis showed no statistically significant associations of plasma omega-6 or omega-3 levels with cardiac magnetic resonance imaging measures. Stratification by gender revealed a positive association between DHA and LV mass in women (β = 1.89, P = 0.02; P interaction = 0.003) and a trend for a positive association between DHA and ejection fraction in men (β = 0.009, P = 0.05; P interaction = 0.03). Conclusion. Additional research is warranted to clarify the effects of plasma DHA on cardiac structure and function in women versus men.
doi:10.1155/2011/315134
PMCID: PMC3159987  PMID: 21869927

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